Details of the Drug Combination

General Information of Drug Combination (ID: DCSE08L)

• Drug Combination Name: Tucatinib + Gemfibrozil
• Indication: Drug-drug Interaction; Status: Phase 1 [1]
• Component Drugs:
  Tucatinib (DMBESUA): N.A.
  Gemfibrozil (DMD8Q3J): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Tucatinib

Disease Entry	ICD 11	Status	REF
HER2-positive breast cancer	2C60-2C65	Approved	[2]
Gastric adenocarcinoma	2B72	Phase 2/3	[3]

Tucatinib Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Erbb2 tyrosine kinase receptor (HER2)	TT6EO5L	ERBB2_HUMAN	Inhibitor	[2]

Indication(s) of Gemfibrozil

Disease Entry	ICD 11	Status	REF
Hyperlipidaemia	5C80	Approved	[4]

Gemfibrozil Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Lipoprotein lipase (LPL)	TTOF3WZ	LIPL_HUMAN	Activator	[7]

Gemfibrozil Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[9]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[9]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[10]
UDP-glucuronosyltransferase 1A9 (UGT1A9)	DE85D2P	UD19_HUMAN	Metabolism	[9]
Catechol-2,3-dioxygenase (caD)	DEFKSVZ	A0A371SLU3_9BACI	Metabolism	[11]

Gemfibrozil Interacts with 18 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[6]
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Increases Expression	[6]
Aldo-keto reductase family 1 member B10 (AKR1B10)	OTOA4HTH	AK1BA_HUMAN	Decreases Activity	[12]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Decreases Activity	[13]
Bifunctional epoxide hydrolase 2 (EPHX2)	OTPTRCNW	HYES_HUMAN	Affects Expression	[14]
Cytochrome P450 2J2 (CYP2J2)	OTJBTEH8	CP2J2_HUMAN	Affects Expression	[14]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Increases Expression	[15]
Phospholipid-transporting ATPase ABCA1 (ABCA1)	OT94G6BQ	ABCA1_HUMAN	Increases Expression	[16]
Apolipoprotein A-I (APOA1)	OT5THARI	APOA1_HUMAN	Increases Expression	[17]
Apolipoprotein B-100 (APOB)	OTH0UOCZ	APOB_HUMAN	Decreases Expression	[17]
Plasminogen activator inhibitor 1 (SERPINE1)	OTT0MPQ3	PAI1_HUMAN	Decreases Expression	[18]
Cytochrome P450 7A1 (CYP7A1)	OT8Z5KLD	CP7A1_HUMAN	Decreases Expression	[19]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Increases Expression	[16]
Oxysterols receptor LXR-beta (NR1H2)	OT4APA60	NR1H2_HUMAN	Increases Expression	[16]
Peroxisome proliferator-activated receptor delta (PPARD)	OTI4WTOP	PPARD_HUMAN	Increases Expression	[16]
Peroxisome proliferator-activated receptor alpha (PPARA)	OTK095PP	PPARA_HUMAN	Increases Expression	[16]
Oxysterols receptor LXR-alpha (NR1H3)	OT54YZ9I	NR1H3_HUMAN	Increases Expression	[16]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Increases Expression	[15]

References

• [1] ClinicalTrials.gov (NCT03723395) A Drug-Drug Interaction Study in Healthy Volunteers of the Effects of Tucatinib
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [3] ClinicalTrials.gov (NCT04499924) Tucatinib, Trastuzumab, Ramucirumab, and Paclitaxel Versus Paclitaxel and Ramucirumab in Previously Treated HER2+ Gastroesophageal Cancer (MOUNTAINEER-02). U.S. National Institutes of Health.
• [4] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 3439).
• [5] Drug-drug interaction potentials of tucatinib inhibition of human UDP-glucuronosyltransferases. Chem Biol Interact. 2023 Aug 25;381:110574. doi: 10.1016/j.cbi.2023.110574. Epub 2023 May 30.
• [6] Comparative effects of fibrates on drug metabolizing enzymes in human hepatocytes. Pharm Res. 2005 Jan;22(1):71-8.
• [7] Mode of action of fibrates in the regulation of triglyceride and HDL-cholesterol metabolism. Drugs Today (Barc). 2006 Jan;42(1):39-64.
• [8] Clinical pharmacokinetics of fibric acid derivatives (fibrates). Clin Pharmacokinet. 1998 Feb;34(2):155-62.
• [9] The UDP-glucuronosyltransferase 2B7 isozyme is responsible for gemfibrozil glucuronidation in the human liver. Drug Metab Dispos. 2007 Nov;35(11):2040-4.
• [10] Comprehensive pharmacogenomic study reveals an important role of UGT1A3 in montelukast pharmacokinetics. Clin Pharmacol Ther. 2018 Jul;104(1):158-168.
• [11] Genomic, proteomic, and metabolite characterization of gemfibrozil-degrading organism Bacillus sp. GeD10. Environ Sci Technol. 2016 Jan 19;50(2):744-55.
• [12] Inhibiting wild-type and C299S mutant AKR1B10; a homologue of aldose reductase upregulated in cancers. Eur J Pharmacol. 2008 Apr 28;584(2-3):213-21.
• [13] Cytochrome P450 inhibition potential of new psychoactive substances of the tryptamine class. Toxicol Lett. 2016 Jan 22;241:82-94.
• [14] Expression of cytochrome P450 epoxygenases and soluble epoxide hydrolase is regulated by hypolipidemic drugs in dose-dependent manner. Toxicol Appl Pharmacol. 2018 Sep 15;355:156-163.
• [15] Effect of common medications on the expression of SARS-CoV-2 entry receptors in liver tissue. Arch Toxicol. 2020 Dec;94(12):4037-4041. doi: 10.1007/s00204-020-02869-1. Epub 2020 Aug 17.
• [16] On the mechanism for PPAR agonists to enhance ABCA1 gene expression. Atherosclerosis. 2009 Aug;205(2):413-9. doi: 10.1016/j.atherosclerosis.2009.01.008. Epub 2009 Jan 19.
• [17] Niacin, but not gemfibrozil, selectively increases LP-AI, a cardioprotective subfraction of HDL, in patients with low HDL cholesterol. Arterioscler Thromb Vasc Biol. 2001 Nov;21(11):1783-9. doi: 10.1161/hq1001.096624.
• [18] Effects of fibrate compounds on expression of plasminogen activator inhibitor-1 by cultured endothelial cells. Arterioscler Thromb Vasc Biol. 1999 Jun;19(6):1577-81. doi: 10.1161/01.atv.19.6.1577.
• [19] Fibrates modify the expression of key factors involved in bile-acid synthesis and biliary-lipid secretion in gallstone patients. Eur J Clin Pharmacol. 2004 Feb;59(12):855-61. doi: 10.1007/s00228-003-0704-1. Epub 2003 Dec 18.